Intracellular Microenvironment Research Articles

Mycobacterium tuberculosis Fatty Acyl-CoA Synthetase fadD33 Promotes Bacillus Calmette-Guérin Survival in Hostile Extracellular and Intracellular Microenvironments in the Host.

Tuberculosis, caused by Mycobacterium tuberculosis (M. tb), remains a significant global health challenge. The survival of M. tb in hostile extracellular and intracellular microenvironments is crucial for its pathogenicity. In this study, we discovered a Bacillus Calmette-Guérin (BCG) mutant B1033 that potentially affected mycobacterium pathogenicity. This mutant contained an insertion mutation gene, fadD33, which is involved in lipid metabolism; however, its direct role in regulating M. tb infection is not well understood. Here, we found that the absence of fadD33 reduced BCG adhesion and invasion into human pulmonary alveolar epithelial cells and increased the permeability of the mycobacterial cell wall, allowing M. tb to survive in the low pH and membrane pressure extracellular microenvironment of the host cells. The absence of fadD33 also inhibited the survival of BCG in macrophages by promoting the release of proinflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumors necrosis factor-α, through the mitogen-activated protein kinase p38 signaling pathway. Overall, these findings provide new insights into M. tb mechanisms to evade host defenses and might contribute to identifying potential therapeutic and vaccine targets for tuberculosis prevention.

Multimodal Nanoplatform with ROS Amplification to Overcome Multidrug Resistance in Prostate Cancer via Targeting P-Glycoprotein and Ferroptosis.

Chemotherapy remains the most essential treatment for prostate cancer, but multidrug resistance (MDR) contributes to chemotherapy failure and tumor-related deaths. The overexpression of P-glycoprotein (P-gp) is one of the main mechanisms behind MDR. Here, this work reports a multimodal nanoplatform with a reactive oxygen species (ROS) cascade for gas therapy/ferroptosis/chemotherapy in reversing MDR. The nanoplatform disassembles when responding to intracellular ROS and exerts three main functions: First, nitric oxide (NO) targeted delivery can reverse MDR by downregulating P-gp expression and inhibiting mitochondrial function. Second, ferrocene-induced ferroptosis breaks the redox balance in the tumor intracellular microenvironment and synergistically acts against the tumor. Third, the release of paclitaxel (PTX) is precisely controlled in situ in the tumor for chemotherapy that avoids damage to normal tissues. Excitingly, this multimodal nanoplatform is a promising weapon for reversing MDR and may provide a pioneering paradigm for synergetic cancer therapy.

A triple-targeting fluorescent probe reveals the glutathione and viscosity crosstalk in mitochondria, endoplasmic reticulum, and nucleoli in cells during ferroptosis

Ferroptosis, a recently termed cell death form, is featured by iron accumulation and lipid peroxidation, which plays various roles in physiological and pathological processes such as cancer evolution and therapy. Redox homeostasis profoundly varies in cells during ferroptosis, but many events remain to be explored, especially at the sub-cellular level. Glutathione (GSH) is the most abundant bio-reductant and mainly distributes in mitochondria (Mito), endoplasmic reticulum (ER), and nucleoli (Nuc) except the cytoplasm. The GSH level is intrinsically related to the redox equilibriums in the three organelles. Viscosity is an index of the intracellular micro-environments related to redox homeostasis. The dynamics of the GSH and viscosity levels in organelles are vital to understanding cell ferroptosis but are in a veil due to the lack of the appropriate tools. Here we report a fluorescent probe (FPY) with dual-response to GSH and viscosity, characteristic of the triple-targeting to Mito, ER, and Nuc. We apply FPY in fluorescent imaging of cells during ferroptosis and disclose the GSH-viscosity crosstalk at the sub-cellular level. We discover an abnormal GSH recruitment in Nuc from the cytoplasm in the late stage of ferroptosis.

Cellular Membrane-Engineered Nanovesicles as a Three-Stage Booster to Targetthe Lesion Core.

The lesion core is the area with the most serious injury and vigorous repair. Existing nanocarriers are difficult to break through the targeted delivery to the lesion core for precise treatment in the intracellular and extracellular microenvironment. Herein, a cellular membrane-engineered nanovesicle (CMEV) with a hierarchical structure is constructed using the double emulsion-extrusion method by integrating a neutrophil membrane, functional antibody, and gelled drug-loaded core as a three-stage booster to target the lesion core and deliver catestatin (CST), a small therapeutic peptide, for ischemic cardiomyopathy therapy. By coating the neutrophil membrane outside the shell, CMEV is endowed with the function of neutrophil-like migration to achieve the first stage of tissue targeting. Based on the specific anchoring to injured myocardium, a myosin light chain 3 (MLC3) antibody is embedded to fulfill the second stage of CMEV accumulation in the lesion core. The gelled core containing CST-sodium alginate (NaAlg) with a pH-responsive shell is prepared by ionic cross-linking to accomplish the third stage of precise CST administration. Triggered by the microenvironment, NaAlg electrostatically adheres to the lesion core for sustained release, enhancing the efficacy of CST in improving cardiomyocyte apoptosis, excessive fibrosis, macrophage polarization, and angiogenesis. Thus, the "three-stage booster" nanovesicle significantly ameliorates cardiac function and adverse remodeling to treat ischemic cardiomyopathy.

Biomolecular condensates in kidney physiology and disease.

The regulation and preservation of distinct intracellular and extracellular solute microenvironments is crucial for the maintenance of cellular homeostasis. In mammals, the kidneys control bodily salt and water homeostasis. Specifically, the urine-concentrating mechanism within the renal medulla causes fluctuations in extracellular osmolarity, which enables cells of the kidney to either conserve or eliminate water and electrolytes, depending on the balance between intake and loss. However, relatively little is known about the subcellular and molecular changes caused by such osmotic stresses. Advances have shown that many cells, including those of the kidney, rapidly (within seconds) and reversibly (within minutes) assemble membraneless, nano-to-microscale subcellular assemblies termed biomolecular condensates via the biophysical process of hyperosmotic phase separation (HOPS). Mechanistically, osmotic cell compression mediates changes in intracellular hydration, concentration and molecular crowding, rendering HOPS one of many related phase-separation phenomena. Osmotic stress causes numerous homo-multimeric proteins to condense, thereby affecting gene expression and cell survival. HOPS rapidly regulates specific cellular biochemical processes before appropriate protective or corrective action by broader stress response mechanisms can be initiated. Here, we broadly survey emerging evidence for, and the impact of, biomolecular condensates in nephrology, where initial concentration buffering by HOPS and its subsequent cellular escalation mechanisms are expected to have important implications for kidney physiology and disease.

Dual-channel fluorescent probe for simultaneously detecting H2S and viscosity/polarity and its application in non-alcoholic fatty liver, tumor tissue, and food spoilage

Intracellular hydrogen sulfide (H2S) and micro-environments (e.g. viscosity and polarity) are tightly correlated with various physiological/pathological processes, making them potential biomarkers of many diseases. However, the simultaneously detecting H2S, viscosity, and polarity in inflammation, non-alcoholic fatty liver (NAFL) and tumor tissues containing clinical cancer patient samples has not been achieved yet due to the lack of effective tools. Herein, we presented a mitochondria-targeting near-infrared (NIR) fluorescent probe MQA-DNP) for simultaneously monitoring H2S, viscosity/polarity through dual channels. The probe could specifically recognize H2S via far-red emission (λem = 634 nm), and exhibited high sensitivity toward micro-environmental viscosity/polarity in the NIR channel (λem > 714 nm). Facilitated with the probe, we revealed for the first time that inflammation cells and NAFL tissues are accompanied by an up-regulation of H2S, as well as an increase in viscosity level (and/or decrease in polarity degree). Surprisingly, the simultaneous visualization of H2S, viscosity/polarity has also been achieved not only at the cancer cells and tumor models, but also in clinical cancer patients. Compared to detecting a single biomarker, the simultaneous tracking multi-markers through multi-channels seems to be more reliable for visual medical diagnosis of mitochondria-related diseases. Furthermore, inspired by the significant color changes and high sensitivity of MQA-DNP reaction with H2S, MQA-DNP has been successfully used to detect H2S released during food spoilage through test strips, and has great potential for application in complex environments systems.

Reversible modulation of protocell volume via collective response of functional protein in its membrane

Volume change plays an important role in biological cells to regulate their internal microenvironment. To adapt to the rapid variation of the surface area during the volume change, the lipid membrane is dynamically modulated via membrane folding invagination, or spontaneous uptake or release of lipid molecules under osmotic pressure. Here, we demonstrate an alternative approach to design a functional protocellular system capable of dynamically adjusting its volume and intracellular microenvironment in response to the alteration of pH. By assembling and subsequently cross-linking pH-responsive caseinate at the water–oil interface, the caseinate-based protocell with more than ten thousand caseinate units in its membrane was established and showed a reversible volume and pore size change to pH variation due to the collective response of the caseinate in the membrane, which could be used to control the spatial distribution of proto-organelle by regulating of the viscosity inside the protocell.

Formulation of DOX-dimer with bi-functionalized chitooligosaccharide for tumor-specific self-boosted drug release and synergistic chemo/chemodynamic therapy

The toxic side effects and possible drug resistance of the chemotherapeutics hinder their antitumor efficacy. Here, a pH/reactive oxygen species (ROS) dual-triggered nanodrug was developed for the tumor-specific self-boosted drug release and synergistic chemo/chemodynamic therapy, by formulating ROS-cleavable doxorubicin (DOX)-based dimer (DOX-TK-DOX) with bi-functionalized chitooligosaccharide (COS-Fc-TK) with ferrocenecarboxylic acid (Fc) and thioketal (TK). The resultant DOX-TK-DOX/COS-Fc-TK nanoparticles with a high DOX content of 39.70 % showed tumor-specific self-boosted drug release, which was triggered by highly toxic OH generated via Fc-catalyzed Fenton reaction of the endogenous H2O2 in tumor intracellular microenvironment. As a result, a synergistic chemo/chemodynamic therapy with combination index (CI) of 0.94 was achieved for selective treatment of tumors.

Clearance of intracellular bacterial infections by hyaluronic acid-based ROS responsive drug delivery micelles

Pathogenic bacteria residing inside cells could cause disruption of cellular metabolic balance. Therefore, basing on high oxidative stress response of the intracellular bacteria infected micro-environment, a novel amphipathic micelle (HATAD-TCS) was developed consisting of hyaluronic acid-derivative and reactive oxygen species (ROS) - responsive group and antibacterial agent triclosan (TCS). ROS-generating cinnamaldehyde (CA) was incorporated into ROS-cleavable linkages which are future linked to the 1-decylamine to form hydrophobicity. The cinnamaldehyde released did not just killed bacteria however, also maintained intracellular ROS levels. In this study, the HATAD-TCS micelles have been characterized by scanning electron microscopy (SEM) and dynamic light scattering (DLS). The HATAD-TCS micelles could release drug gradually upon exposure to endogenous ROS being caused by infected intracellular bacteria. Furthermore, the more promising therapeutic effect of the HATAD-TCS micelles was observed in a mouse pneumonia model. These results might highlight a ROS-responsive hyaluronic acid-based nanoparticle, which could effectively treat intracellular bacterial infections.

Intracellular Hyperbranched Polymerization for Circumventing Cancer Drug Resistance.

Polymerization inside living cells provides chemists with a multitude of possibilities to modulate cell activities. Considering the advantages of hyperbranched polymers, such as a large surface area for target sites and multilevel branched structures for resistance to the efflux effect, we reported a hyperbranched polymerization in living cells based on the oxidative polymerization of organotellurides and intracellular redox environment. The intracellular hyperbranched polymerization was triggered by reactive oxygen species (ROS) in the intracellular redox microenvironment, effectively disrupting antioxidant systems in cells by an interaction between Te (+4) and selenoproteins, thus inducing selective apoptosis of cancer cells. Importantly, the obtained hyperbranched polymer aggregated into branched nanostructures in cells, which could effectively evade drug pumps and decrease drug efflux, ensuring the polymerization for persistent treatment. Finally, in vitro and in vivo studies confirmed that our strategy presented selective anticancer efficacy and well biosafety. This approach provides a way for intracellular polymerization with desirable biological applications to regulate cell activities.

Lipid mediators in the regulation of innate and adaptive immunity.

Lipid mediators in the regulation of innate and adaptive immunity.

Kinetics and Mechanism of Camptothecin Release from Transferrin-Gated Mesoporous Silica Nanoparticles through a pH-Responsive Surface Linker.

Stimuli-responsive nanomaterials have emerged as a promising strategy for inclusion in anticancer therapy. In particular, pH-responsive silica nanocarriers have been studied to provide controlled drug delivery in acidic tumor microenvironments. However, the intracellular microenvironment that the nanosystem must face has an impact on the anticancer effect; therefore, the design of the nanocarrier and the mechanisms that govern drug release play a crucial role in optimizing efficacy. Here, we synthesized and characterized mesoporous silica nanoparticles with transferrin conjugated on their surface via a pH-sensitive imine bond (MSN-Tf) to assess camptothecin (CPT) loading and release. The results showed that CPT-loaded MSN-Tf (MSN-Tf@CPT) had a size of ca. 90 nm, a zeta potential of -18.9 mV, and a loaded content of 13.4%. The release kinetic data best fit a first-order model, and the predominant mechanism was Fickian diffusion. Additionally, a three-parameter model demonstrated the drug-matrix interaction and impact of transferrin in controlling the release of CPT from the nanocarrier. Taken together, these results provide new insights into the behavior of a hydrophobic drug released from a pH-sensitive nanosystem.

Research Models to Study Ferroptosis's Impact in Neurodegenerative Diseases.

Ferroptosis is a type of regulated cell death promoted by the appearance of oxidative perturbations in the intracellular microenvironment constitutively controlled by glutathione peroxidase 4 (GPX4). It is characterized by increased production of reactive oxygen species, intracellular iron accumulation, lipid peroxidation, inhibition of system Xc-, glutathione depletion, and decreased GPX4 activity. Several pieces of evidence support the involvement of ferroptosis in distinct neurodegenerative diseases. In vitro and in vivo models allow a reliable transition to clinical studies. Several in vitro models, including differentiated SH-SY5Y and PC12 cells, among others, have been used to investigate the pathophysiological mechanisms of distinct neurodegenerative diseases, including ferroptosis. In addition, they can be useful in the development of potential ferroptosis inhibitors that can be used as disease-modifying drugs for the treatment of such diseases. On the other hand, in vivo models based on the manipulation of rodents and invertebrate animals, such as Drosophila melanogaster, Caenorhabditis elegans, and zebrafish, have been increasingly used for research in neurodegeneration. This work provides an up-to-date review of the main in vitro and in vivo models that can be used to evaluate ferroptosis in the most prevalent neurodegenerative diseases, and to explore potential new drug targets and novel drug candidates for effective disease-modifying therapies.

Cobweb‐Inspired Microenvironment‐Targeting Nanosystem with Sequential Multiple‐Stage Stimulus‐Response Capacity for Ischaemic Tissue Repair

AbstractMyocardial ischaemia is pathologically complicated; various changes in intracellular and extracellular microenvironments make it essential to develop a smart drug system with multiple stimulus responses to adapt to the complex process. Inspired by the cobweb, this study designs a microreticular nanosystem that adheres to tissue and is sequentially responsive to multiple stimuli in the ischaemic microenvironment. The nanosystem is fabricated from hyaluronic acid (HA), ROS‐responsive B‐PDEA, and hypoxia‐sensitive VEGF‐expressing plasmids (EPODNA) through electrostatic interactions. After intramyocardial injection, the tissue‐adhesive property of the nanosystem will significantly decrease its acute loss from the injection site. Extracellularly, the microreticular nanosystem first responds to activated hyaluronidase (hyal), releasing HA for microenvironment regulation and B‐PDEA/DNA nanoparticles (NP) with high transfection efficiency for cardiac cells. Intracellularly, ROS sequentially induced B‐PDEA/DNA NP dissociation, consuming some ROS to attenuate oxidative stress and releasing DNA to promote its expression. Meanwhile, local hypoxia significantly activates VEGF expression in plasmids for myocardial revascularization and repair. The function of the microreticular nanosystem is systematically evaluated in vitro. In a rat model of myocardial infarction, treatment with the microreticular nanosystem significantly promotes functional and structural improvements. Collectively, the study provides a promising smart nanosystem to promote tissue repair after complex damage.

Nanomaterials against intracellular bacterial infection: from drug delivery to intrinsic biofunction.

Fighting intracellular bacteria with strong antibiotics evading remains a long-standing challenge. Responding to and regulating the infectious microenvironment is crucial for treating intracellular infections. Sophisticated nanomaterials with unique physicochemical properties exhibit great potential for precise drug delivery towards infection sites, along with modulating infectious microenvironment via their instinct bioactivity. In this review, we first identify the key characters and therapeutic targets of intracellular infection microenvironment. Next, we illustrate how the nanomaterials physicochemical properties, such as size, charge, shape and functionalization affect the interaction between nanomaterials, cells and bacteria. We also introduce the recent progress of nanomaterial-based targeted delivery and controlled release of antibiotics in intracellular infection microenvironment. Notably, we highlight the nanomaterials with unique intrinsic properties, such as metal toxicity and enzyme-like activity for the treatment of intracellular bacteria. Finally, we discuss the opportunities and challenges of bioactive nanomaterials in addressing intracellular infections.

Green synthesized polyvinylpyrrolidone/titanium dioxide hydrogel nanocomposite modified with agarose macromolecules for sustained and pH-responsive release of anticancer drug

Cancer, as one of the most challenging diseases of the last century, has a significant number of patients and deaths every year. Various strategies have been explored for the treatment of cancer. Chemotherapy is one of the methods of treating cancer. Doxorubicin is one of the compounds used in chemotherapy to kill cancer cells. Due to their unique properties and low toxicity, metal oxide nanoparticles are effective in combination therapy and increase the effectiveness of anti-cancer compounds. The limited in vivo circulatory period, poor solubility, and inadequate penetration of doxorubicin (DOX) restrict its use in cancer treatment, notwithstanding its attractive characteristics. It is possible to circumvent some of the difficulties in cancer therapy by using green synthesized pH-responsive nanocomposite consisting of polyvinylpyrrolidone (PVP), titanium dioxide (TiO2) modified with agarose (Ag) macromolecules. TiO2 incorporation into the PVP-Ag nanocomposite resulted in limited increased loading and encapsulation efficiencies from 41 % to 47 % and 84 % to 88.5 %, respectively. DOX diffusion among normal cells is prevented by the PVP-Ag-TiO2 nanocarrier at pH = 7.4, though the acidic intracellular microenvironments activate the PVP-Ag-TiO2 nanocarrier at pH = 5.4. Characterization of the nanocarrier was performed using X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectrophotometry, field emission scanning electron microscopy (FE-SEM), dynamic light scattering (DLS), and zeta potential. The average particle size and the zeta potential of the particles showed values of 349.8 nm and +57 mV, respectively. In vitro release after 96 h showed a release rate of 92 % at pH 7.4 and a release rate of 96 % at pH 5.4. Meanwhile, the initial release after 24 h was 42 % for pH 7.4 and 76 % for pH 5.4. As shown by an MTT analysis on MCF-7 cells, the toxicity of DOX-loaded PVP-Ag-TiO2 nanocomposite was substantially greater than that of unbound DOX and PVP-Ag-TiO2. After integrating TiO2 nanomaterials into the PVP-Ag-DOX nanocarrier, flow cytometry data showed a greater stimulation of cell death. These data indicate that the DOX-loaded nanocomposite is a suitable alternative for drug delivery systems.

Targeting hPKM2 in cancer: A bio isosteric approach for ligand design

The term cancer refers to a plethora of diseases characterized by the development of abnormal cells that divide uncontrollably and can infiltrate further proximal or distal body tissues. Each type of cancer can be defined by aggressiveness, localization, metabolism, and response to available treatments. Among the most common hallmarks of cancer is a more acidic intracellular microenvironment. Offset pH values are due to an excess of lactate and an increased hypoxia-inducible factor (HIF) expression, which leads to a hypoxic state and a metabolic shift towards glycolysis to produce adenosine-5′-triphosphate (ATP) necessary for cellular metabolism. Warburg's hypothesis underpins this concept, making glycolysis and its central enzyme pyruvate kinase (hPKM2), an ideal target for drug development. Using molecular docking and extensive molecular dynamics (MD) simulations we investigated the binding mode of phosphoenolpyruvate (PEP) inside the hPKM2 active site, and then evaluated a set of known bio-isosteric inhibitors to understand the differences caused by their substitutions on their binding mode. Ultimately, we propose a new molecular entity to hamper hPKM2, unbalance cellular energy, and possibly trigger autophagic mechanisms.

Arginine deiminase pathway of Tetragenococcus halophilus contributes to improve the acid tolerance of lactic acid bacteria

Arginine deiminase pathway, controlled by arginine deiminase, ornithine carbamoyltransferase and carbamate kinase, could affect and modulate the intracellular pH homeostasis of lactic acid bacteria under acid stress. Herein, strategy based on exogenous addition of arginine had been proposed to improve the robustness of Tetragenococcus halophilus during acid stressed condition. Results indicated cells cultured in the presence of arginine acquired high tolerance to acid stress mainly through maintaining the homeostasis of intracellular microenvironment. Additionally, metabolomic analysis and q-PCR showed the content of intracellular metabolites and expression levels of genes involved in ADI pathway significantly increased when cells encountered acid stress with the presence of exogenous arginine. Furthermore, Lactococcus lactis NZ9000 with heterologous overexpression of arcA and arcC from T. halophilus exhibited high stress tolerance to acidic condition. This study may provide an insight into the systematical understanding about the mechanism underlying acid tolerance and improve the fermentation performance of LAB during harsh condition.

Multifunctional Fluorescent Probe for Simultaneous Detection of ONOO-, Viscosity, and Polarity and Its Application in Ferroptosis and Cancer Models.

Intracellular peroxynitrite anions (ONOO-) and microenvironments (such as viscosity and polarity) play an important role in maintaining redox homeostasis, regulating diffusion, transportation, and signal transduction in living cells. The abnormality of these factors is often closely related to various physiological/pathological processes. However, owing to the lack of suitable probes, the simultaneous visualization of ONOO-, viscosity, and polarity in ferroptosis and cancer models has not been achieved. To meet urgent needs, we presented a multifunctional near-infrared (NIR) fluorescent probe, named MQA-P, for simultaneously detecting ONOO-, viscosity, and polarity within mitochondria. The probe exhibited a remarkable turn-on response to ONOO- with the far-red emission of about 645 nm and was highly sensitive to viscosity/polarity in the NIR channel with λem > 704 nm. Facilitated by MQA-P, for the first time, we revealed that erastin-induced ferroptosis was accompanied by a significant upregulation of ONOO- and an increase of viscosity (or decrease of polarity) at the same time. Moreover, the concurrent use of ONOO-, viscosity, and polarity for the diagnosis of cancer has been successfully achieved not only at cell/tissue levels but also in tumor mice models. Compared with detecting only one factor, this simultaneous detection of multimarkers provides a more sensitive and reliable method/tool for tracking ferroptosis-related pathological processes and cancer diagnosis, holding great potential in preclinical research, medical diagnosis, and imaging-guided surgery.

Mesoporous TiO2 Coatings Regulate ZnO Nanoparticle Loading and Zn2+ Release on Titanium Dental Implants for Sustained Osteogenic and Antibacterial Activity.

Two major issues are currently hindering the clinical practice of titanium dental implants for the lack of biological activities: immediate/early loading risks and peri-implantitis. To solve these issues, it is urgent to develop multifunctional implants modified with effective osteogenic and antibacterial properties. Zinc oxide nanoparticles (ZnO NPs) possess superior antibacterial activity; however, they can rapidly release Zn2+, causing cytotoxicity. In this study, a potential dental implant modification was creatively developed as ZnO nanoparticle-loaded mesoporous TiO2 coatings (nZnO/MTC-Ti) via the evaporation-induced self-assembly method (EISA) and one-step spin coating. The mesoporous TiO2 coatings (MTCs) regulated the synthesis and loading of ZnO NPs inside the nanosized pores. The synergistic effects of MTC and ZnO NPs on nZnO/MTC-Ti not only controlled the long-term steady-state release of Zn2+ but also optimized the charge distribution on the surface. Therefore, the cytotoxicity of ZnO NPs was resolved without triggering excessive reactive oxygen species (ROS). The increased extracellular Zn2+ further promoted a favorable intracellular zinc ion microenvironment through the modulation of zinc transporters (ZIP1 and ZnT1). Owing to that, the adhesion, proliferation, and osteogenic activity of bone mesenchymal stem cells (BMSCs) were improved. Additionally, nZnO/MTC-Ti inhibited the proliferation of oral pathogens (Pg and Aa) by inducing bacterial ROS production. For in vivo experiments, different implants were implanted into the alveolar fossa of Sprague-Dawley rats immediately after tooth extraction. The nZnO/MTC-Ti implants were found to possess a higher capability for enhancing bone regeneration, antibiosis, and osseointegration in vivo. These findings suggested the outstanding performance of nZnO/MTC-Ti implants in accelerating osseointegration and inhibiting bacterial infection, indicating a huge potential for solving immediate/early loading risks and peri-implantitis of dental implants.